Cardiac Effects of Attenuating Gsα - Dependent Signaling

PLoS One. 2016 Jan 26;11(1):e0146988. doi: 10.1371/journal.pone.0146988. eCollection 2016.

Abstract

Aims: Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.

Methods and results: We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation.

Conclusion: Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists
  • Animals
  • Cardiomegaly / chemically induced
  • Cardiomegaly / metabolism
  • Cell Size
  • Cyclic AMP / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Gene Expression
  • Heart Rate
  • Isoproterenol / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardium / metabolism*
  • Myocytes, Cardiac / physiology
  • Signal Transduction
  • Stroke Volume
  • Ventricular Function, Left
  • Ventricular Pressure

Substances

  • Adrenergic beta-Agonists
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gs
  • Isoproterenol

Grants and funding

The work presented herein was in part supported by the Deutsche Forschungsgemeinschaft (HA 2959/2-2, and HA 2959/3-1 within the DFG-Forschergruppe 1036), by a research grant from the Ernst-und-Berta-Grimmke foundation (SEH), and by a research grant of the Deutsche Herzstiftung e.V (CSW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.